N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as Wnt signaling modulators

Abstract

The present invention relates to methods for modulating the Wnt signaling pathway using compounds of Formula (1), wherein A 1 , Y and Z all represent rings.

The invention claimed is: 
     
       1. A method for treating a Wnt-mediated disorder in a subject suffering therefrom, comprising administering to the subject a compound of Formula (6), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         X 1 , X 2 , X 3  and X 4  is selected from N and CR 7 ; 
         one of X 5 , X 6 , X 7  and X 8  is N and the others are CH; 
         X 9  is selected from N and CH; 
         Z is selected from phenyl, pyrazinyl, pyridinyl, pyridazinyl and piperazinyl; wherein each phenyl, pyrazinyl, pyridinyl, pyridazinyl or piperazinyl of Z is optionally substituted with an R 6  group; 
         R 1 , R 2  and R 3  are hydrogen; 
         m is 1; 
         R 4  is selected from hydrogen, halo, difluoromethyl, trifluoromethyl and methyl; 
         R 6  is selected from hydrogen, halo and —C(O)R 10 ; wherein R 10  is methyl; and 
         R 7  is selected from hydrogen, halo, cyano, methyl and trifluoromethyl; 
         and optionally in combination with a chemotherapeutic agent; 
         wherein said Wnt-mediated disorder is colorectal cancer, colorectal carcinoma, breast cancer, head and neck squamous cell carcinoma, pancreatic cancer, melanoma, or head and neck cancer. 
       
     
     
       2. The method of  claim 1 , wherein said compound is 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof. 
     
     
       3. The method of  claim 2 , wherein said compound is a fumaric acid salt. 
     
     
       4. The method of  claim 1 , wherein said compound is N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)acetamide, or a pharmaceutically acceptable salt thereof. 
     
     
       5. The method of  claim 4 , wherein said compound is a fumaric acid salt. 
     
     
       6. The method of  claim 1 , wherein said Wnt-mediated disorder is breast cancer. 
     
     
       7. The method of  claim 1 , wherein said Wnt-mediated disorder is head and neck squamous cell carcinoma. 
     
     
       8. The method of  claim 1 , wherein said Wnt-mediated disorder is melanoma. 
     
     
       9. The method of  claim 1 , wherein said Wnt-mediated disorder is pancreatic cancer. 
     
     
       10. A combination comprising a therapeutically effective amount of a compound of Formula (6), 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , X 2 , X 3  and X 4  is selected from N and CR 7 ; 
         one of X 6 , X 6 , X 7  and X 8  is N and the others are CH; 
         X 9  is selected from N and CH; 
         Z is selected from phenyl, pyrazinyl, pyridinyl, pyridazinyl and piperazinyl; wherein each phenyl, pyrazinyl, pyridinyl, pyridazinyl or piperazinyl of Z is optionally substituted with an R 6  group; 
         R 1 , R 2  and R 3  are hydrogen; 
         m is 1; 
         R 4  is selected from hydrogen, halo, difluoromethyl, trifluoromethyl and methyl; 
         R 6  is selected from hydrogen, halo and —C(O)R 10 ; wherein R 10  is methyl; and 
         R 7  is selected from hydrogen, halo, cyano, methyl and trifluoromethyl; 
         or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent. 
       
     
     
       11. The combination of  claim 10 , wherein said compound is 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide, or a pharmaceutically acceptable salt thereof. 
     
     
       12. The combination of  claim 11 , wherein said compound is fumaric acid salt.